Many methods are known for the treatment of fungal infections, including the oral and topical use of antibiotics (e.g. nystatin and amphotericin B), imidazole antifungal agents such as miconazole, clotrimazole, fluconazole, econazole and sulconazole, and non-imidazole fungal agents such as the allylamine derivatives terbinafine and naftifine, and the benzylamine butenafine.
Onychomycosis is a fungal infection of the nail unit caused by yeast, dermatophytes, or other molds, and represents approximately 50% of all nail disorders. Toenail infection accounts for approximately 80% of onychomycosis incidence, while fingernails are affected in about 20% of the cases. Dermatophytes are the most frequent cause of nail plate invasion, particularly in toenail onychomycosis. Onychomycosis caused by a dermatophyte is termed tinea unguium. Trichophyton rubrum is by far the most frequently isolated dermatophyte, followed by T. mentagrophytes. Distal subungual onychomycosis is the most common presentation of tinea unguium, with the main site of entry through the hyponychium, progressing in time to involve the nail bed and the nail plate. The disease is characterized by discoloration, onycholysis, accumulation of subungual debris and nail plate dystrophy. Diagnosis can be confirmed by KOH (potassium hydroxide) preparations and mycologic culture. The disease adversely affects the quality of life of its victims, with subject complaints ranging from unsightly nails and discomfort with footwear, to more serious complications including secondary bacterial infections.
Onychomycosis has proved to be resistant to treatment. Nail fungal infections reside in an area difficult to access by conventional topical treatment, and antifungal drugs cannot readily penetrate the nail plate to reach the infection sites under the nail. Therefore, onychomycosis has traditionally been treated by oral administration of antifungal drugs; however, clearly this is undesirable due to the potential for side effects of such drugs, in particular those caused by the more potent antifungal drugs such as itraconazole and ketoconazole. An alternative method of treatment of onychomycosis is by removal of the nail before treating with a topically active antifungal agent; such a method of treatment is equally undesirable.
Onychomycoses do not resolve spontaneously, and even if successfully treated, tend to recur. Treatment of onychomycosis is often a challenging endeavor for the clinician. Systemic antimycotic agents require prolonged use and have the potential for significant side effects. Topical agents have usually been of little benefit.
It would therefore be advantageous to have a topical formulation that is capable of penetrating the nail barrier and effectively treating nail fungal diseases, thus avoiding oral administration of antifungal drugs and the necessity of removing the nail. It would be preferable if such treatment required only nightly applications of the formulation, i.e. effective treatment did not require that the formulation be resident 24 hours per day on the nails over a long period of time. This patent application describes such a formulation.
Publications of interest are WO 96/19186, U.S. Pat. No. 4,746,509, U.S. Pat. No. 4,822,822, U.S. Pat. No. 5,322,685, PCT Application US92/10989, EP Patent Application 55,397, GbB2, 202, 743A; and CA 1,175,355.